Lactones of 1, 12-dimethyl-6, 10-dihydroxy-9-oxo-1, 2, 3, 4, 9, 10, 11, 12-octahydrophenanthrene-1-carboxylic acid



United States Patent LACTONES 0F 1,12 DIMETHYL 6,10 DIHY- DROXY 9 0X01,2,3,4,9,10,11,12 OCTAHY- DROPHENANTHRENE 1 CARBOXYLIC ACID Roy H.Bible, Jr., Morton Grove, Ill., assignor, by mesne assignments, to G. D.Searle & C0., Skokie, 111., a corporation of Delaware ApplicationNovember 26, 1954, Serial No. 471,523

5 Claims. (Cl. 260343.3)

N 0 Drawing.

This invention pertains to a new group of lactones related to1,12-dimethyl-6,10-dihydroxy-9-oxo-l,2,3,4,9,l0,ll,lZ-octahydrophenanthrene-l-carboxylic acid and lower alkyl ethersthereof. It is specifically concerned with lactones having thestructural formula OR CH OR CH3 1120 COOH wherein R is a member of thegroup consisting of hydrogen and lower alkyl radicals.

For some purposes the lactones which comprise this invention are alsoequivalent to the hydroxy carboxylic acids which can be represented bythe structural formula OR CH3 HsC O O O H OH wherein R is a member ofthe group consisting of hydrogen and lower alkyl radicals, and which arerelated to the lactones by a process of intramolecular dehydration.

Although for certain applications, such as reactions involvingtransesterifications, the latter two structural species may play animportant role, I have found that ice the lactonic forms of thesecompounds are more stable under normal condtions and I have developedmethods for preparing these lactones in good yield and in high states ofpurity.

A suitable starting material for preparing the compounds of thisinvention is an alkyl O-alkylpodocarpate, such as methylO-methylpodocarpate. An oxo group is first introduced into the9-position by means of a controlled oxidation with chromium trioxide.When this 9-oxo derivative is brominated in a halogenated hydrocarbonsolvent with a selective brominating agent such as N-bromosuccinimide, abromine atom is introduced into the l0-position. When the resultingmethyl ester of 1,12-dimethyl 6 methoxy-9-oxo-l0-bromo-l,2,3,4,9,10,l1,1.2-octahydrophenanthrene-l-carboxylic acid is heated with anitrogenous base such as 2,4,6-trimethylpyridine, ring closure occurswith the loss of the elements of methyl bromine and the formation of thedesired lactone.

In an alternative method for the preparation of the lactones whichcomprise this invention, an O-alkylpodocarpic acid such asO-methylpodocarpic acid is converted to the 9-0Xo derivative withchromium trioxide, and the resulting1,lZ-dimethyl-6-methoxy-9-oxo-1,2,3,4,9,10,1 1,l2-octahydrophenanthrene-l-carboxylic acid is treated withN-bromosuccinimide. While an intermediate 10- bromo derivative isbelieved to exist in this reaction mixture, elimination of the bromineatom as hydrogen bromide and ring closure occur spontaneously, with theresult that the lactone can be isolated directly from the mixture.

In preparing the lactone of this invention wherein R is hydrogen, thatis, the lactone of 1,12-dimethyl-6,l0- dihydroxy 9 oxo1,2,3,4,9,l0,11,12-octahydrophenanthrene-l-carboxylic acid, it ispreferred to dealkylate a corresponding 6-alkoxy derivative by suchmeans as heating it with a mixture of glacial acetic acid andhydrobromic acid.

The compounds which constitute this invention have valuable hormonal andanti-inflammatory properties. Specifically, they have been found toinhibit the hyperemia that is associated with states of inflammation ofthe iris. The claimed compounds are also useful as intermediates inchemical syntheses.

My invention will appear in greater detail from the following examples.However, it is not to be construed as limited thereby in spirit or inscope. In these examples temperatures are given in degrees centigradeand quantities of materials are given in parts by Weight.

Example 1 A solution of 100 parts of methyl O-methylpodocarpate in 1050parts of hot glacial acetic acid is stirred and cooled to 17 C. andtreated at that temperature, by slow addition, with 72 parts of chromiumtrioxide in 166 parts of acetic acid in the course of 30 minutes.Stirring is continued for another 10 minutes after which the mixture isstored at 5 C. for 3 days and then at room temperature for 2 days. It isthen poured with stirring into 1000 parts of ice-cold water andextracted with ether. The ether extract is washed with 10% aqueoussodium hydroxide until the washings are no longer colored and then withwater to neutrality. The washed ether solution is dried over anhydrouscalcium sulfate, filtered and stripped of solvent under vacuum. Theslightly yellow solid residue is recrystallized twice from aqueousethanol to yield clusters of beautiful white prisms melting at about122-124 C. A 1% solution in absolute alcohol gives a specific rotationof +124". The infrared spectrum exhibits strong bands at 5.82, 6.02,6.28, 6.39, and 6.76 microns. The ultraviolet spectrum shows a peak at227 millimicrons with a molecular extinction coeflicient of 13,000 and apeak at 276 millimicrons with a molecular extinction coeflicient of15,800. The methyl ester of OCHs OH: I

HBO/\C 0 0113 Example 2 A mixture of 4.9 parts of the methyl ester of1,12-dimethyl 6methoxy-9-oxo-1,2,3,4,9,10,11,12-octahydrophenanthrene-1-carboxylic acidand 2.8 parts of N-bromosuccinimide in 80 parts of anhydrous carbontetrachloride is allowed to stand, with occasional stirring, at roomtemperature for 30 hours. This reaction is promoted by light, and forgood results it is advisable to expose the mixture tosunlight for asubstantial portion of the reaction time. At the end of this period oftime the succinirnide formed in the reaction is removed by filtration;it amounts to about 1.3 parts. The solvent is removed from the filtrateby a vacuum distillation, leaving a residual yellow oil which graduallycrystallizes. This brominated derivative is purified byrecrystallization from aqueous methanol. In this manner it is obtainedas well-formed needles which, after thorough drying, melt at about142-1445 C. This methyl ester of 1,l2-dimethyl-6-meth0xy-9-0X0-l0-bromo-1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid has thestructural formula OOH:

CH3 l A mixture of 3.0 parts of the methyl ester of 1,12- dimethyl 6methoxy-9-oxo-l0- romo-1,2,3,4,9,10,l1,l2-octahydrophenanthrene-l-carboxylic acid, and 23 parts of2,4,6-trimethylpyridine is heated under reflux for a period of 2 hours.The mixture is then poured, with stirring, into 200 parts of water, andthe resulting suspension is acidified with dilute hydrochloric acid. Thealmost colorless precipitate which remains is collected on a filter. Forpurification, it is recrystallized from a mixture of benzene andpetroleum ether. Another good method of purification is by sublimationin a vacuum. The purified material melts at 198200.5 C. and exhibits aspecific rotation of about +85 Ultraviolet absorption maxima areobserved at 231 and 291 millimicrons. Infrared absorption maxima appearat 5.67, 6.93, 6.25, and 6.39 microns. This compound is the lactone of1,12-dimethyl 6 methoxy-9-oxo-l0-hydroxy1,2,3,4,9,10,11,12-octahydrophenanthrene-l-carboxylic acid and it has the followingstructural formula OCH:

Example 4 A solution of parts of O-methylpodocarpic acid and 1070 partsof glacial acetic acid is stirred and maintained at 1518 C. while asolution of 65.4 parts of chromium trioxide in a mixture of 32 parts ofwater and 134 parts of glacial acetic acid is added in the course of 30minutes. The reaction mixture is stirred at 5l0 C. and then stored at810 C. for 3 days. After further storage at room temperature for 2 days,40 parts of ethanol are added slowly with good mixing in order todecompose any unreacted chromium trioxide. The entire reaction mixtureis stirred into 3000 parts of warm water and then extracted exhaustivelywith ether. The combined ether extracts are washed with dilutehydrochloric acid until the washings are no longer colored and then withWater to neutrality. The solution is dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to yield a light yellow,viscous oil. The product is decolorized by boiling a methanolic solutionwith activated charcoal. The 1,12-dimethyl-6-methoxy-9-oxo-l,2,3,4,9,10,11,1Z-octahydrophenanthrene-l-carboxylic acid crystallizes fromaqueous methanol in small, colorless, gleaming prisms which melt atabout 183-185 C. The infrared spectrum shows well-defined bands at 2.83,5.90, 5.98, 6.27, and 7.82 microns. The ultraviolet absorption spectrumhas peaks at 226 and 276 millimicrons with molecular extinctioncoeificients of 13,600 and 15,700.

respectively. The compound has the structural formula 0 CH: OH:

HaC C O OH Example 5 A slurry prepared from 4.00 parts of1,12-dimethyl-6- methoxy-9-oxo-1,2,3,4,9,10,1 1,l2-octahydrophenanthrenel-carboxylic acid, 2.52 parts ofN-bromosuccinimide and 320 parts of anhydrous carbon tetrachloride isallowed to stand, with occasional stirring, for 30 hours at roomtemperature. This reaction is promoted by light, and for good results itis advisable to expose the mixture to sunlight for a substantial portionof the reaction time. The precipitated material, which consists largelyof succinimide, is collected on a filter and the desired reactionproduct is recovered from the filtrate after removal of the solvent by avacuum distillation. The residual material, by recrystallization fromaqueous methanol, gives the same purified lactone of1,12-dimethyl-6-methoxy-9-oxo-10- hydroxy 1,2,3,4,9,10,1l,12octahydrophenanthrene 1 carboxylic acid that is obtained by theprocedure of Example 3. When the residue obtained by evaporation of thecrystallization liquors is extracted with dilute sodium hydroxidesolution, the fraction which remains undissolved by this treatmentyields more of the pure lactone when it is recrystallized from aqueousmethanol.

Example 6 To a solution of 400 parts of methyl podocarpate and 120 partsof sodium hydroxide in 1100 parts of water and 1600 parts of 95% ethanolare added all at once 330 parts of diethyl sulfate. The reactants arequickly mixed and then allowed to stand until a thick white precipitateforms. This precipitate is collected on a filter, washed with diluteethanol, and recrystallized from methanol to yield methylO-ethylpodocarpate as thin, colorless needles melting at about 144147.5C.

A stirred solution of parts of methyl O-ethylpodocarpate in 1000 partsof hot glacial acetic acid is cooled to 15 C. and treated at thattemperature with 68 parts of chromium trioxide in 156 parts of 80%acetic acid in the course of 30 minutes. Stirring is continued for a fewmore minutes after which the mixture is maintained at 10 C. for 2 daysand then at room temperature for 2 days. It is then poured, withstirring, into 1000 parts of ice and water and extracted with ether.This extract is washed with 10% aqueous potassium hydroxide until thewashings are colorless and then with water to neutrality. The ethersolution is dried over anhydrous calcium sulfate, filtered andconcentrated in vacuo. When the residual methyl ester of1,12-dimethy1-6- ethoxy-9-oxo-l,2,3,4,9,l0,11,12octahydrophenanthrenel-carboxylic acid is treated withN-bromosuccinimide by the procedure of Example 2, and the resultantmethyl ester of 1,1Z-dimethyl-6-ethoxy-9-oxo-10-bromo-1,2,3,4,9,l0,1l,12-octahydrophenanthrene-l-carboxylic acid is treated withboiling 2,4,6-trimethylpyridine by the procedure of Example 3, there isobtained the lactone of 1, lZ-dimethyl-6-ethoxy-9-oxo-10-hydroxy-1,2,3,4 ,9', 10, 1 1, 1Z-octahydrophenanthrene-l-carboxylicacid. This compound has the following structural formula Example 7 Amixture of parts of the lactone of 1,12-dimethyl- 6-methoxy-9 oxohydroxy-1,2,3,4,9,10,11,12-octahydrophenanthrene-l-carboxylic acid, 37parts of glacial acetic acid and 30 parts of 48% hydrobromic acid isheated under reflux for a period of 1 hour. The reaction mixture is thencooled and poured, with stirring, into about 350 parts of water. Theinsoluble material is washed by decantation with several portions offresh water and it is then extracted with mixtures of chloroform andether. The organic solution is washedwith dilute potassium bicarbonatesolution and then with several portions of water. All aqueous washingsare discarded. When the organic phase is dried, filtered and evaporatedto dryness there is obtained a crystallizate of a lactone of1,12-dimethyl-6,10-dihydroxy-9-oxo-1,2,3,4,9,10,11,12-octahydr0phenanthrene 1 carboxylic acid in which thehydroxyl group participating in laetone formation is that occupying the10-position. This compound has the following structural formula OH CH:

6 I claim:

1. A compound having the structural formula OR CH;

structural formula HaC C- wherein R is a member of the group consistingof hydrogen and lower alkyl radicals, the steps which comprisedissolving a compound having the structural formula 0 R CH1 H O COOR'wherein R and R are each members of the group consisting of hydrogen andlower alkyl radicals, in a halogenated hydrocarbon solvent, mixing thesolution thus obtained with N-bromosuccinimide, and allowing it to standin the presence of light.

References Cited in the file of this patent UNITED STATES PATENTSRitchie Mar. 8, 1955 Bible et a1. Apr. 5, 1955 OTHER REFERENCES Zeiss:Chem. Reviews, vol. 42, pp. 163-87 (1948). Pschorr: Berichte, 39, pp.3106-24 (1906).

1. A COMPOUND HAVING THE STRUCTURAL FORMULA